gut hormones in obesity, nicotine and alcohol dependence

Conditions: Obesity; Smoking Cessation; Alcoholism

Summary: the "gut hormones in addiction" study is a proof-of-concept experimental medicine human study to answer the following questions: 1. does the administration of the hormone desacyl ghrelin reduce core behavioural components of addiction in dependent individuals who have recently stopped smoking tobacco or drinking alcohol, or overweight/obese subjects? 2. does the administration of the drug exenatide reduce core behavioural components of addiction in dependent individuals who have recently stopped smoking tobacco or drinking alcohol, or overweight/obese subjects? 3. does the administration of desacyl ghrelin or exenatide reduce reward responses to high-calorie foods and appetite in dependent individuals who have recently stopped smoking tobacco or drinking alcohol, or overweight/obese subjects?

obesity, smoking and alcohol dependence are major health burdens to society. relapse after alcohol and smoking abstinence is common despite the use of combined behavioural support and current limited available medications. in obesity, nonsurgical interventions have also been disappointing in achieving longterm weight loss. therefore, there is a pressing need to develop novel drug treatments for addiction derived from knowledge of brain mechanisms related to relapse and reward responses to food and drugs. there is evidence in animals that some gut hormones, produced in the stomach and intestine, influence the consumption of food and desire for food, but also alcohol, nicotine and other drugs of abuse. examples of such gut hormones are glucagon-like peptide1 (glp1) and ghrelin. the influence of these hormones is exerted through brain systems involved in the core behavioural components of addiction: reward sensitivity, stress, impulsivity and compulsivity. these components are often also seen in obesity and food-related disorders such as binge eating disorder. it is unknown whether these gut hormones directly influence the core behavioural components of addiction in humans, particularly during abstinence. the investigators will examine the acute effects of exenatide (mimics glp1) and desacyl ghrelin (counteracts active acyl ghrelin), which are infused through a vein, on brain reward systems, craving for food, cigarettes and alcohol, and addictive and eating behaviours. the investigators will recruit adults with nicotine or alcohol dependence who have recently stopped smoking or drinking, and overweight/obese adults. the investigators will use functional magnetic resonance imaging (mri) brain scans and computer-based test over 3 separate study days to study different aspects of eating and addictive behaviours.

Eligibility criteria:
inclusion criteria: 1. male or female volunteers between the ages of 18 and 60 years. 2. healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests, cardiac monitoring and a psychiatric evaluation. any volunteer with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included, only if the investigators concur that the finding is unlikely to jeopardize either volunteer safety or study integrity. 3. the subject is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. 4. the subject is able to read, comprehend and record information written in english. 5. for non-dependent groups: i) overweight/obese volunteers with bmi 28.0-50.0 kg/m2. 6. for addiction groups: subjects meeting diagnostic and statistical manual (dsm)-v criteria for previous nicotine or alcohol dependence, but who are in early stable abstinence (\>6 weeks). minor lapses within this time period will be allowed but not relapses into dependence. ii) abstinent alcohol dependent individuals who score at least moderately alcohol dependent as measured retrospectively using the severity of alcohol dependence questionnaire (sadq), and who have been abstinent for \>6 weeks. iii) abstinent tobacco dependent individuals who score at least moderately on tobacco dependence as measured retrospectively using the fagerström test for nicotine dependence (ftnd), and who have been in stable tobacco abstinence for \>6 weeks. exclusion criteria: potential volunteers will not be eligible for inclusion in this study if any of the following criteria apply: 1. previous history of recreational use or abuse of other substances of addiction will be permissible, but there should be no use of any illegal drugs (except cannabis) in the month prior to the screening visit or during the course of the study, except where specified for individual groups below. 2. for individual groups: i) overweight/obese group: history of or current alcohol abuse or dependence; nicotine use other than "never smoked", i.e. \>100 cigarettes lifetime use; history of dependence, abuse or heavy recreational use of cocaine, cannabis, opiates or other substance of abuse; history of problem gambling. any previous or current psychiatric diagnosis listed in diagnostic and statistical manual (dsm)-v axis i, which in the opinion of the clinical team will compromise conduct and interpretability of the study. ii) abstinent tobacco dependent group: history of or current alcohol abuse or dependence; current dependence for cocaine, cannabis, opiates or other substance of abuse, or problem gambling (previous history will be allowed); taking varenicline, bupropion or other prescription medications for smoking cessation. any previous or current psychiatric diagnosis listed in diagnostic and statistical manual (dsm)-v axis i, which in the opinion of the clinical team will compromise conduct and interpretability of the study. iii) abstinent alcohol dependent group: current dependence for cocaine, cannabis, opiates or other substance of abuse, or problem gambling (previous history will be allowed); taking prescription medication for alcohol or smoking cessation or withdrawal; smoking is allowed past or present including dependence; current nicotine replacement therapy is allowed. 3. currently suffering from diagnostic and statistical manual (dsm)-v depressive disorder or on anti-depressant medication, though a history of depression or anxiety will be allowed. a current or past history of enduring severe mental illness (e.g., schizophrenia, bipolar affective disorder) will not be allowed. for all groups: 4. cannabis use up to five times in the month prior to the screening visit will be allowed, but no use within one week of experimental assessments; no use of any other illegal drugs in the month prior to the screening visit or during the course of the study. 5. intoxication at any of the visits, as manifested by difficulty in walking, slurring of speech, difficulty concentrating or drowsiness (or by the subject volunteering this information directly to the research team). 6. positive drug/alcohol screens on testing at the screening visit, other than that explicable by other causes (e.g. recent use of opiate containing analgesic etc), at the discretion of the research team. 7. carbon monoxide levels of =/\>10ppm in the overweight/obese and abstinent smoker groups at screening visit. 8. use of current regular prescriptions (including smoking or alcohol cessation medicines such as disulfiram, acamprosate, naltrexone, bupropion; weight loss medication including orlistat, metformin, glp-1 agonists, bupropion, naltrexone), or over-the-counter medications that in the opinion of the investigators may affect subject safety or outcome measures. 9. pulse rate \ 100 beats per minute or systolic blood pressure \>160 and \ 95 and \<50 in the semi-supine position. 10. claustrophobia or feels that they will be unable to lay still on their back in the mri scanner for a period of \~80 minutes. 11. presence of a cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies as assessed by a standard pre-mri questionnaire and radiographer. 12. history or presence of a neurological diagnosis (not limited to but including, for example, stroke, epilepsy, space occupying lesions, multiple sclerosis, parkinson's disease, vascular dementia, transient ischemic attack, that may influence the outcome or analysis of the scan results). a history of alcohol-related or alcohol-withdrawal seizures will be allowed for volunteers in the abstinent alcoholic group. 13. significant current or past medical or psychiatric history that, in the opinion of the investigators, contraindicates their participation. 14. clinically significant head injury (e.g. requiring hospitalisation or surgical intervention) that in the opinion of the investigators may affect subject safety or outcome measures. 15. unwillingness or inability to follow the procedures outlined in the protocol. 16. any of the following liver function tests (lft) abnormalities at screening: alkaline phosphatase, aspartate aminotransferase (ast), alanine aminotransferase (alt) or gammagt \> 4 x upper limit of normal (uln), international normalised ratio (inr) \> 1.5, albumin \<25 g/l, raised bilirubin (other than just isolated i.e. without other liver function tests abnormalities). 17. history of decompensated alcoholic liver disease - i.e. history of variceal bleeding, ascites, jaundice, encephalopathy. 18. history of pancreatitis from any cause. 19. history of type 1 or type 2 diabetes mellitus. 20. ecg abnormality, which in the opinion of the study physician, is clinically significant and represents a safety risk. 21. the volunteer has participated in a clinical trial and has received an investigational product within the following time period prior to the first experimental visit in the current study: 90 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). 22. exposure to more than 3 new investigational medicinal products within 12 months prior to the scan. 23. history of sensitivity to any of the peptides, or components thereof, or a history of drug or other allergy that, in the opinion of the investigators, contraindicates their participation. 24. diagnosis of endocrine disorder, including uncontrolled hypothyroidism (stable treated hypothyroidism with currently normal thyroid function tests is allowed), history of hyperthyroidism or cushing's syndrome, which, in the opinion of the investigators, may affect subject safety or outcome measures. 25. history of ischaemic heart disease, heart failure, cardiac arrhythmia or peripheral vascular or cerebrovascular disease. 26. history or presence of significant respiratory, gastrointestinal, hepatic, oncological or renal disease or other condition that in the opinion of the investigators may affect subject safety or outcome measures. 27. previous bariatric surgery for obesity including roux-en-y gastric bypass, gastric banding, sleeve gastrectomy. 28. current pregnancy or breast-feeding in female volunteers. 29. vegetarian, vegan, gluten or lactose-intolerant. 30. volunteers who have donated, or intend to donate, blood within three months before the screening visit or following study visit completion.

Keywords: tobacco glp1 ghrelin alcohol appetite reward addiction hormone cigarette functional mri